PRC2 molecule EED is a target of epigenetic therapy of neuroblastoma
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PROVIDER: PRJNA760445 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic modification by polycomb repressive complex (PRC) molecules appears to have a role in tumorigenesis and aggressiveness of neuroblastoma (NB). Embryonic Ectoderm Development (EED) is a member of PRC2 complex and binds the H3K27me3 mark deposited by EZH2, via propagation on adjacent nucleosomes. Here we studied the molecular roles of EED in MYCN-amplified neuroblastoma cells by using EED-knocked down shRNAs, EED-knocked out sgRNAs, and EED small molecule inhibitor EED226. EED suppression profoundly inhibited the NB cell proliferation and flat-and soft agar colony formation. Transcriptome analysis by microarray of the EED-KD NB cells indicated the de-repression of the cell cycle regulated and differentiation-related genes; GSEA analysis results suggested that cell cycle repressed gene sets were strongly upregulated. Further, epigenetic treatment by the combination of EED inhibitor EED226 and HDAC inhibitor valproic acid effectively suppressed NB cell proliferation and colony formation. The combinatory epigenetic treatment up-regulated the cell cycle regulation- and differentiation-related genes.
2022-09-03 | GSE183369 | GEO
Project description:PRC2 molecule EZH1 is a target of epigenetic therapy of neuroblastoma
| PRJNA779921 | ENA
Project description:In the present study, we found that EZH1 depletion in MYCN-amplified neuroblastoma cells resulted in significant cell death as well as xenograft inhibition. EZH1 depletion decreased the level of H3K27me1; the interaction and protein stabilization of MYCN and EZH1 appear to play roles in epigenetic transcriptional regulation. Transcriptome analysis of EZH1-depleted cells resulted in down-regulation of the cell cycle progression-related pathway. In particular, GSEA revealed down-regulation of reactome E2F-mediated regulation of DNA replication along with key genes of this process, TYMS, POLA2, and CCNA1. TYMS and POLA2 were transcriptionally activated by MYCN and EZH1-related epigenetic modification. Treatment with the EZH1/2 inhibitor UNC1999 also induced cell death, decreased H3K27 methylation, and reduced the levels of TYMS in NB cells. Previous reports indicated neuroblastoma cells are resistant to 5-fluorouracil (5-FU) and TYMS (encoding thymidylate synthetase) has been considered the primary site of action for folate analogues. Intriguingly, UNC1999 treatment significantly sensitized MYCN-amplified neuroblastoma cells to 5-FU treatment, suggesting that EZH inhibition may be an effective strategy for development of a new epigenetic treatment for neuroblastoma.
2022-11-08 | GSE188673 | GEO
Project description:The Polycomb Repressive Complex 2 (PRC2) regulates corticogenesis, yet how PRC2 influences cell identity in the mature brain is poorly defined. Using a mouse model in which the PRC2 gene Eed is conditionally deleted from the developing mouse dorsal telencephalon, we performed single nuclei RNA sequencing on the cortical plate of adult heterozygote and homozygote Eed knockout mice compared to controls.
2024-09-11 | GSE276683 | GEO
Project description:Analysis of changes in gene expression in skin epidermis upon conditional knockout of the essential Polycomb repressive complex 2 (PRC2) subunit Eed. Loss of Eed in skin epithelium leads to de-repression of key Merkel-differentiation genes, which are known PRC2 targets, and results in ectopic formation of Merkel cells that are associated with all hair types. Gene expression analysis: To determine the changes in gene expression in skin epidermis upon conditional knockout of Eed, total RNA was isolated from skin epidermis in four biologic replicates from cells in different conditions and hybridized to SurePrint G3 Mouse GE 8X60K microarrays (Agilent).
2016-06-14 | E-GEOD-83244 | biostudies-arrayexpress
Project description:Polycomb repressive complex 2 (PRC2) is a chromatin-modifying enzyme that catalyzes the methylation of lysine 27 on histone H3 (H3K27me1/2/3). This complex maintains the gene expression profiles in different cell types and plays an essential role in normal organismal development. The mechanisms by which PRC2 targets specific chromatin regions remain unclear. To address this question, we focused on the post-translational modifications (PTMs) of PRC2 subunits. Here we show EED, a core component of PRC2, is acetylated by acetyltransferase CBP/P300 at lysine 19 (K19). The acetylation of EED at K19 (EED-K19ac) reduces the binding affinity between PRC2 and native nucleosomes, causing PRC2 to leave its chromatin targets in vivo. Genome-wide location analysis (ChIP-seq) reveals that K19-acetylated EED preferentially accumulates at highly transcribed genes with low EZH2 and H3K27me3 levels. Using CRISPR/Cas9 technology, we generated mouse embryonic stem cells (mESCs) carrying non-acetylated EED mimic (EED-K19R) and showed acetylation of EED at K19 is necessary for mESC differentiation. In summary, our study reveals a novel mechanism that allows intracellular signalling pathways to regulate cellular differentiation and cell fate decisions by controlling the genomic targeting of PRC2 through acetylating EED.
2023-09-30 | GSE160211 | GEO
Project description:Polycomb repressive complex 2 (PRC2) is a chromatin-modifying enzyme that catalyzes the methylation of lysine 27 on histone H3 (H3K27me1/2/3). This complex maintains the gene expression profiles in different cell types and plays an essential role in normal organismal development. The mechanisms by which PRC2 targets specific chromatin regions remain unclear. To address this question, we focused on the post-translational modifications (PTMs) of PRC2 subunits. Here we show EED, a core component of PRC2, is acetylated by acetyltransferase CBP/P300 at lysine 19 (K19). The acetylation of EED at K19 (EED-K19ac) reduces the binding affinity between PRC2 and native nucleosomes, causing PRC2 to leave its chromatin targets in vivo. Genome-wide location analysis (ChIP-seq) reveals that K19-acetylated EED preferentially accumulates at highly transcribed genes with low EZH2 and H3K27me3 levels. Using CRISPR/Cas9 technology, we generated mouse embryonic stem cells (mESCs) carrying non-acetylated EED mimic (EED-K19R) and showed acetylation of EED at K19 is necessary for mESC differentiation. In summary, our study reveals a novel mechanism that allows intracellular signalling pathways to regulate cellular differentiation and cell fate decisions by controlling the genomic targeting of PRC2 through acetylating EED.
2023-09-30 | GSE160210 | GEO
Project description:Squamous cell carcinoma (SCC) is a common epithelial malignancy, yet its epigenetic underpinnings remain poorly defined. Here, we identify the Polycomb Repressive Complex 2 (PRC2) as a key epigenetic barrier of SCC tumorigenesis. Despite high EZH2 levels, the PRC2-dependent H3K27me3 is depleted in human and murine SCCs, indicating complex destabilization rather than enzymatic failure. Mechanistically, oncogenic Ras signaling downregulates the PRC2 scaffolding subunit EED, disrupting PRC2 and H3K27me3 and activating oncogenic loci. Depletion of Eed in epidermal progenitors disrupts the proliferation–differentiation balance and, upon carcinogen exposure, drives invasive SCC. Single-cell RNA-seq of Eed-deficient tumors reveals an expansion of tumor-specific keratinocytes and a remodeled pro-tumorigenic microenvironment. Notably, reintroducing EED in SCC cells restores PRC2 integrity and H3K27me3 levels, suppressing tumor growth and mitigating the pro-tumorigenic niche. Our findings establish PRC2 as an essential epigenetic gatekeeper in SCC and suggest restoring PRC2-mediated repression may offer a novel therapeutic strategy.
2026-06-13 | GSE304812 | GEO
Project description:Analysis of changes in gene expression in skin epidermis upon conditional knockout of the essential Polycomb repressive complex 2 (PRC2) subunit Eed. Loss of Eed in skin epithelium leads to de-repression of key Merkel-differentiation genes, which are known PRC2 targets, and results in ectopic formation of Merkel cells that are associated with all hair types.
2016-06-14 | GSE83244 | GEO
Project description:Squamous cell carcinoma (SCC) is a common epithelial malignancy, yet its epigenetic underpinnings remain poorly defined. Here, we identify the Polycomb Repressive Complex 2 (PRC2) as a key epigenetic barrier of SCC tumorigenesis. Despite high EZH2 levels, the PRC2-dependent H3K27me3 is depleted in human and murine SCCs, indicating complex destabilization rather than enzymatic failure. Mechanistically, oncogenic Ras signaling downregulates the PRC2 scaffolding subunit EED, disrupting PRC2 and H3K27me3 and activating oncogenic loci. Depletion of Eed in epidermal progenitors disrupts the proliferation–differentiation balance and, upon carcinogen exposure, drives invasive SCC. Single-cell RNA-seq of Eed-deficient tumors reveals an expansion of tumor-specific keratinocytes and a remodeled pro-tumorigenic microenvironment. Notably, reintroducing EED in SCC cells restores PRC2 integrity and H3K27me3 levels, suppressing tumor growth and mitigating the pro-tumorigenic niche. Our findings establish PRC2 as an essential epigenetic gatekeeper in SCC and suggest restoring PRC2-mediated repression may offer a novel therapeutic strategy.
2026-06-13 | GSE305085 | GEO